The long term goal of this project is to discover improved medical treatments for central neurodegenerative disorders affecting motor and cognitive function. Novel strategies to symptom palliation and neuroprotection are currently being explored. Efforts to develop alternative approaches to the symptomatic treatment of Parkinson's disease continue to make steady progress. Previous results suggested that an enhanced synaptic efficacy of glutamate receptors, especially those of the NMDA subtype on striatal medium spiny neurons, contributes to the motor dysfunction attending nigrostriatal dopamine system degeneration as well as to the response complications associated with standard dopaminomimetic therapy. Since the sensitivity of these receptors is regulated by their phosphorylation state, ongoing studies have attempted to link alterations in motor function with the activity of kinases and phosphatases capable of interacting with specific serine/threonine and tyrosine residues on NMDAR2A and NMDAR2B subunits. Our results now suggest that the augmented sensitivity of NMDA receptors on D1 receptor expressing spiny neurons in parkinsonian rats with response alterations mimicking those occurring in parkinsonian patients reflects increased serine phosphorylation as a consequence of cyclic AMP-protein kinase A activation. Inhibition of this enzyme, a component of the cAMP cascade linked to dopamine receptors, reversed the response alterations. We further found that striatal NMDA receptor function is enhanced by tyrosine phosphorylation of NR2B subunits, first as a consequence of the decline in nigral dopaminergic input and later following chronic exposure to intermittent (non-physiologic) dopaminergic stimulation and onset of the characteristic motor response alterations. Expression of NR2A subunit protein increased with dopaminergic denervation, but normalized with subsequent levodopa therapy. Intrastriatal injection of a tyrosine kinase inhibitor, at a dose that normalized the motor response alterations, significantly attenuated the phosphorylation increase. Controlled proof of principle trials, based on our findings in parkinsonian rats and primates, reported during the past year of two subunit nonselective NMDA antagonists, dextrorphan and dextromethorphan, showed substantial relief of disability, albeit with a therapeutic index that limits clinical usefulness. A third trial with a long-marketed NMDA antagonist, amantadine, proved even more successful, producing substantial and persistent clinical benefit rivaling that obtained from surgical approaches. These pioneering studies provide strong support for our view that supersensitivity of NMDA receptors contributes to the pathogenesis of human levodopa-associated motor complications and that blockade of these receptors can substantially reduce disability. NF-kB cascade activation appears to participate in the apoptotic demise of human nigral dopaminergic and striatal GABAergic neurons and thus might serve as a novel target for neuroprotective intervention. Our evaluation of mechanisms playing a role in the NMDA receptor-mediated activation of rat NF-kB now indicates that neurotoxic doses of quinolinic acid substantially reduced cytoplasmic IkB concentrations and increased nuclear NF-kB binding activity. Concentrations of c-Myc and p53 increased at the same time that internucleosomal DNA fragmentation became evident. Blocking NF-kB nuclear translocation attenuated the excitotoxin-induced c-Myc and p53 elevations as well as internucleosomal DNA fragmentation. NMDA receptor stimulation may thus trigger striatal neuron apoptosis as a result of IkB degradation, NF-kB translocation, and c-Myc and p53 induction. We also found that the NMDA receptor-mediated generation of reactive oxygen species contributes to the quinolinic-induced activation of NF-kB and that oral administration of a potent new-generation free radical scavenger protects against excitotoxin-induced apoptosis of rat striatal neurons through inhibition of the NF-kB apoptotic cascade. The therapeutic implications of these findings are now being explored in rodent and primate models.